Facile and Rapid Synthesis of Polysubstituted Imidazoles by Employing Y ( NO 3 ) 3 × 6 H 2 O as Catalyst

An efficient and environmentally adapted synthesis of polysubstituted imidazoles in one-pot and multicomponent reaction of various aldehydes, benzil, aliphatic and aromatic primary amines and ammonium acetate under solvent-free condition is reported. Highly efficient role of Y(NO3)3 ×6H2O as catalyst in this synthesis was shown. By this advantage, several polysubstituted imidazoles as pharmaceutical important molecules can be prepared in high yield and high purity. This method is very easy and rapid for the synthesis of imidazole derivatives. All products were deduced from their IR and NMR spectroscopic and elemental analysis data. The catalyst exhibited remarkable reusable activity. (doi: 10.5562/cca1979)


INTRODUCTION
Multicomponent reactions (MCRs) are the special type of organic reactions which afford complex products from reaction of three or more simple starting materials in one pot.Because of atom-economy, convergent character, operational simplicity, structural diversity and complexity of the molecules in these reactions, they have attracted much attention. 1,2he imidazoles and their derivatives are very important molecules because many applications in chemical processes, especially in pharmaceuticals. 3,4Various substituted imidazoles act as inhibitors of p38 MAP kinase, 5 B-Raf kinase, 6 glucagon receptors, 7 plant growth regulators, 8 antitumor 9 and pesticides. 10here are many methods for the synthesis of polysubstituted imidazoles such as condensation of diones, aldehydes, primary amines and ammonia in the presence of various acid catalysts, [11][12][13] N-alkylation of trisubstituted imidazoles, 14 condensation of benzil or benzoin acetate with aldehydes, primary amines and ammonia in the presence of copper acetate 15,16 etc.The first mention method is the most well-known and classical method.
However, some of these methods, involved long reaction times, and unsatisfactory yields.Therefore, improvements in these syntheses have been sought continuously.In this work, high activation, and reusability of Y(NO 3 ) 3 ×6H 2 O as a catalyst in the synthesis of polysubstituted imidazoles have been shown.
A new method for the synthesis of polysubstituted imidazoles was obtained by condensation of benzil with aldehydes, primary amines and ammonium acetate in the presence of Y(NO 3 ) 3 ×6H 2 O as an effective catalyst in solvent free condition (Scheme 1).
Herein, we report a simple, rapid and one-pot procedure for the synthesis of three and four substituted imidazoles by using Y(NO 3 ) 3 ×6H 2 O with high yields and short reaction times.While using benzil 1, aromatic aldehydes 2, aromatic and aliphatic amine 3, ammonium acetate 4 and Y(NO 3 ) 3 ×6H 2 O as catalyst under solventfree condition lead to tetrasubstituted imidazoles 5, that in the absence of aromatic and aliphatic amine 3, trisubstituted imidazoles 6 were obtained (Scheme 1).

EXPERIMENTAL SECTION
Melting points were measured on an elecrtothermal KSB1N apparatus.IR spectra were recorded in the matrix of KBr with JASCO FT-IR-680 plus spectrometer. 1 H NMR and 13 C NMR spectra were recorded on a FT-NMR Bruker Avance Ultra Shield Spectrometer at 400.13 and 100.62 MHz in CDCl 3 and DMSO-d 6 as solvent in the presence of tetramethylsilane as internal standard.TLC was performed on TLC-Grade silica gel-G/UV 254 nm plates.The products were isolated and characterized by physical and spectral data and they were compared with authentic samples (   A mixture of aromatic aldehyde (1 mmol), benzil (1 mmol), primary amine (1 mmol), ammonium acetate (1 mmol) and Y(NO 3 ) 3 ×6H 2 O (mole ratio, r = 15 %) were stirred at 140 °C in solvent-free condition.The progress of reaction was monitored by TLC.After completion of reaction, the mixture was coolled to room temperature and was solved in 50 mL water then was filtered.Obtained products were purified by crystallization from acetone-water mixture (V(acetone) : V(water) =10 : 1).][19][20][21][22][23][24][25][26][27] Hence, general procedure for the synthesis of 2,4,5-trisubstituted imidazoles is same to the 1,2,4,5tetrasubstituted imidazoles, but it needs to 10 % of catalyst, 2 mmol of ammonium acetate instead of 1 mmol in the absence of primary amine.

RESULTS AND DISCUSSION
Firstly, synthesis of 1-benzyl-2,4,5-triphenyl imidazoles was chosen as a model reaction (compound 5a) in the synthesis of polysubstituted imidazoles to determine the optimum condition for this synthesis.In model reaction, in the presence of Y(NO 3 ) 3 ×6H 2 O (15 %) as catalyst, the mixture of benzil (1 mmol), benzaldehyde (1 mmol), ammonium acetate (1 mmol), benzylamine (1 mmol) carried out in different solvents such as water, ethanol, methanol, chloroform, acetonitrile and solvent-free conditions.From these experiments, it was clearly demonstrated that the solvent-free conditions offer the best conditions to accomplish this synthesis (Table 2).
Carrying out the model reaction in the absence of catalyst at solvent-free conditions and room temperature for 24 h lead to a very poor yield (12 %) of the product.In the absence of catalyst for enhance the yield of the desired product, temperature of the reaction was increased to 200 °C, but no appreciable increment in the product yield was observed.Therefore, we found that the presence of the catalytic amount of Y(NO 3 ) 3 ×6H 2 O and solvent-free condition are the best conditions for this synthesis.
We also evaluated quantity of required catalyst in synthesis of tetrasubstituted imidazoles for model reaction (compound 5a).It was found that maximum yield (96 %) obtained, when the reaction was carried out with 15 % of Y(NO 3 ) 3 ×6H 2 O, but for the synthesis of 2,4,5trisubtitutedimidazoles, the best amount of the catalyst was found 10 % of catalyst, when the reaction between benzil 1 (1 mmol), aromatic aldehydes 2 (1 mmol) and ammonium acetate 4 (2 mmol) was chosen as a model reaction (Table 3).
We also examined the model reactions at various temperatures to find out its effect on the progress of the reaction in the presence of optimized amount of catalyst (Table 4).The maximum rate of reaction was obtained at 140 °C as the optimum temperature for tri and tetrasubstituted imidazoles.
As can be concluded from Table 4, the reaction proceeded slowly at 80 °C.With increasing temperature to 140 °C, reaction yield was increased and time of reaction was decreased, when the reaction was heated above 140 °C, so high temperatures did not further improved yield and decrease time of reaction.
According to the archived optimal condition, we conducted the synthesis of polysubstituted imidazoles in the presence of Y(NO 3 ) 3 ×6H 2 O as catalyst in solventfree condition at 140 °C.

Reusability of Catalyst
At the end of the reaction, the catalyst was filtered, washed with diethyl ether, dried at 130 °C for 1 h, and reused in another reaction.We found that Y(NO 3 ) 3 ×6H 2 O showed high catalytic activity.Moreover, it can be recovered and reused several times without significant loss of activity.The results of these observations for the model reaction are shown in Table 5.
A probable mechanism for the synthesis of tetrasubstituted imidazoles may be postulated as shown below (Scheme 2).
As can be seen in Scheme 2, Y(NO 3 ) 3 ×6H 2 O is a Lewis acid so that it can activated the carbonyl group of aldehydes 2 to decrease the energy of transition state.Then nucleophilic attack of amine 3 on the activated carbonyl of aldehydes, resulted to the formation of imine, and it followed by nucleophilic attack of the insitu generated ammonia from 4 to the imine, giving the intermediate 7. From condensation of intermediate 7 with benzil 1 and dehydration of it, corresponding imidazoles 5 are produced.
The probable mechanism for synthesis of trisubstituted imidazoles is the same (amine was substituted with ammonium acetate).

Scheme 2 .
Scheme 2. The suggested mechanism for synthesis of tetrasubstituted imidazoles.

Table 2 .
The effect of solvents in synthesis of polysubstituted imidazoles for model reaction

Table 4 .
Optimization of temperature for model reaction

Table 3 .
Optimization of mole ratio of the catalyst in synthesis of tri and tetrasubstituted imidazoles

Table 5 .
Reusability results of Y(NO 3 ) 3 × 6H 2 O on the reaction process for the model reaction